Plasma’s Pivotal Role in Cancer Therapy

PLASMA THERAPY is a promising new treatment for cancer. While plasma therapy itself is not new, its potential to cure myriad cancers is just beginning to be explored.

What makes plasma therapy a viable treatment option for cancer? According to Toby Simon, MD, a medical consultant at the Plasma Protein Therapeutics Association, plasma contains lifesaving properties that, when harnessed through fractionation, produce therapies that are viable options for fighting cancer. “Plasma therapies result from fractionation of the plasma based on changes in temperature, ethanol content, pH and other steps that include chromatography for purification and pathogen reduction for safety,” Dr. Simon explained. “These therapies result in safe and effective parenteral medications with unique properties useful in saving and sustaining lives for many patients.”

A Brief History of Plasma Therapy

Plasma contains antibodies helpful for fighting infections and has been used in some therapeutic capacity for more than a century. According to Plasma Heroes, an educational initiative of the Immune Deficiency Foundation designed to support plasma donation and the patients who rely on plasma-based products, using plasma for therapeutic purposes dates back to 1913 when plasmapheresis (separating the plasma from blood cells) in animal models was originally described, but it was not yet used in humans. However, plasma was given to patients via whole blood transfusions (as in the Spanish influenza pandemic of 1918) until 1938, when researchers discovered how to separate plasma from whole blood in humans.

Not long after that, World War II broke out, greatly increasing the demand for blood and plasma to treat wounded soldiers. During that time, Edwin Cohn, PhD, developed a process called cold ethanol fractionation that separated the proteins in the plasma (albumin, fibrinogen, globulins). Plasma went on to be used to make immune globulin (IG) treatments for primary immunodeficiency diseases in 1952 via intramuscular injection. By 1959, plasmapheresis was used to save the life of an adolescent boy with thrombotic thrombocytopenic purpura (TTP).

The modern plasmapheresis process originated at the U.S. National Cancer Institute between 1963 and 1968. By the 1970s, intravenous IG (IVIG) was introduced. Later, the first studies that demonstrated the anti-cancer effect of gas plasma on tumor cells in rodent models were published in 2010. By 2013, research into plasma oncology was gaining momentum, with studies exploring the effects of cold atmospheric plasma (CAP) on various cancer cells.^1,2,3 To date, there have been many successful examples of using direct plasma therapy for certain types of cancers.

Direct Plasma Therapies

Four types of direct plasma therapies are used to treat different types of cancers:

1) Therapeutic plasma exchange (TPE). TPE is similar to plasmapheresis. However, in TPE, the plasma is discarded completely and is substituted with a replacement fluid, either donor plasma or albumin solution. According to Plasma Heroes, “TPE involves removing some of a patient’s blood. The plasma is separated out from the rest of the blood components, and then the remaining blood cells are put back along with healthy plasma from a plasma donor.”⁴

TPE shows therapeutic value in patients with cancers such as lymphoma, thymoma and multiple myeloma. Harmful antibodies build up in the plasma of patients with these cancers. The antibodies that attack healthy parts of the body are called autoantibodies, and studies show replacing these antibodies has a positive impact on patients. For example, “[Thymoma] cancer causes a person’s immune system to destroy acetylcholine receptors. These receptors are proteins that bind nerves and muscles. In the absence of these receptors, individuals experience muscle weakness and fatigue. TPE can reduce these symptoms by filtering out the autoantibodies that damage these receptors.”⁴

A thymoma is a tumor on the thymus, a small organ that plays a role in the immune system. A common complication of thymoma is the autoimmune disease myasthenia gravis (MG). In MG, the destruction of acetylcholine receptors at the junction of nerves and muscles results in muscle weakness and fatigue. TPE can reduce the symptoms of MG by filtering out the autoantibodies that damage these receptors.⁵

Multiple myeloma involves abnormal cells in the plasma and excess proteins called free light chains (FLCs), which can cause kidney damage by creating casts (obstructions) in the small tubules of the kidneys. TPE can filter out FLCs and prevent kidney damage in multiple myeloma patients.⁵

2) Cold atmospheric plasma (CAP).

CAP is a non-thermal plasma that can be applied directly to tumors or used to create plasma-activated media (PAM), which can then be used to treat cancer cells. CAP is an ionized gas made through gases such as helium, argon and nitrogen and applied at less than 104 degrees Fahrenheit.⁶ Although CAP is a newer treatment currently being tested in U.S. Food and Drug Administration (FDA)-approved clinical trials,⁷ it has shown promise in killing cancer cells, particularly in in vitro and in vivo studies, and is being explored as a potential treatment for various cancers.⁷

CAP contains toxic molecules called reactive oxygen species which target cancerous tissue cells, inducing oxidative stress and damaging the cells in the process. Thus, the cancer cells are no longer able to grow and multiply.⁷ One benefit of CAP is it can identify and destroy cancer cells without harming healthy cells: It can remove very small cancerous tumors that surgeons might have missed, and it does it without causing damage to other parts of the body.⁷

In 2019, FDA approved CAP technology, currently the only way to remove microscopic cancer tumors remaining from surgery, for first-ever use in a clinical trial. According to FDA, “[CAP] technology selectively kills tumors through toxic molecules called reactive oxygen species, which damage targeted cancerous tissue but do not affect normal biological tissue. Lasers could also kill tissue, but the high heat would also bring permanent damage to surrounding tissue.”⁸

Further, a recent study led by Professor Han Wei at the Hefei Institutes of Physical Science of the Chinese Academy of Sciences showed that low-dose CAP treatment could effectively slow down tumor growth: “CAP damages the mitochondria, which are the powerhouses of the cell. This damage messes up the cell’s energy production and causes oxidative stress. The lack of energy and stress on the cells prevents them from dividing properly. This leads to a form of cell death called ‘mitotic catastrophe,’ which stops the tumor from growing.”⁹

CAP has shown to be effective in skin, breast and lung cancers, and, so far, does not seem to be limited to any one type of tumor, so it can potentially work on many other types of cancer as well.

3) Plasma-activated medium (PAM). PAM is a culture medium or liquid that has been treated with a non-thermal atmospheric plasma to create a stable solution of reactive oxygen and nitrogen species (RONS). These RONS give PAM anti-tumor properties by promoting cell death in cancer cells. PAM is used to treat tumors without direct contact with the plasma source. It has shown promising anti-tumor effects, leading to cell death and hindering proliferation in various cancers. It can also enhance the effectiveness of conventional chemotherapies.

PAM has also been found to inhibit the growth and viability of various cancer cells, including glioblastoma, ovarian and gastric cancers. Studies have shown PAM can inhibit the metastasis of ovarian cancer cells and enhance the efficacy of chemotherapy treatments such as carboplatin and cisplatin. PAM treatment has also been shown to reduce endometrial cancer cell viability by inducing autophagic cell death.^10,11 The following studies highlight PAM’s potential as an effective treatment for other cancers:

• A study conducted at the University of Bari Aldo Moro in Bari, Italy, showed how a sealed dielectric-barrier discharge was used to disentangle the effect of reactive nitrogen species (RNS) from that of reactive oxygen species (ROS) on cancer cells. The study investigated metastatic melanoma and pancreatic cancer, two cancers with poor prognoses. According to the study, “Both tumor models exposed to [plasma-activated liquid media] PALM rich in H2O2 showed a reduction in proliferation and an increase in calreticulin exposure and ATP release, suggesting the potential use of activated media as an inducer of immunogenic cell death via activation of the innate immune system.”¹²
• A study conducted at the Islamic Azad University in Tehran, Iran, investigated PAM in an effort to develop more effective treatments for breast cancer. The study investigated the impact of PAM in the presence of doxorubicin (DOX), a chemotherapy drug that has been used to treat various cancers of the breast, head and neck, lung, liver and ovaries. The study investigated the impacts of prepared PAM combined with DOX on the viability of MCF-7 breast cancer cells and showed that “low doses of DOX plus 3-min PAM could be a promising strategy for cancer therapy.”¹³
• Researchers at the Dong-A University in Busan, South Korea, conducted a study on the involvement of ferroptosis, another cell death pathway that is involved in PAM-induced cell death. The study reported, “PAM promotes cell death via ferroptosis in human lung cancer cells, and PAM increases intracellular and lipid ROS, thereby resulting in mitochondrial dysfunction. The treatment of cells with N-acetylcysteine, an ROS scavenging agent, or ferrostatin-1, a ferroptosis inhibitor, protects cells against PAM-induced cell death.” The study demonstrates that “PAM inhibits tumor growth in a xenograft model with an increase in 4-hydroxynoneal and PTGS2, a byproduct of lipid peroxidation, and a decrease in FSP1 expression.”¹⁴

4) Fresh frozen plasma (FFP). FFP is comprised of the liquid component of blood that has been separated from donated whole blood and then frozen within six to eight hours after collection. It contains clotting factors, antibodies and other proteins. FFP is thawed before transfusion, and its administration is indicated for patients with coagulation factor deficiencies, abnormal coagulation test results and active bleeding.

Although FFP is not used as a direct cancer treatment, it can be used as part of a patient’s treatment plan. The main purpose of using FFP in cancer treatment is to help replenish important substances the patient’s body needs that are impacted negatively, not only by the disease itself, but also by other treatments such as chemotherapy. FFP can also enhance the effectiveness of other therapies such as chemotherapy or targeted drugs.

A major component of using FFP is to replace a person’s clotting factors. Cancer treatments such as chemotherapy can lower blood cell counts, which directly affects the body’s ability to make clotting factors. FFP is also used to treat disseminated intravascular coagulation, as well as TTP.¹⁵

Phase II of a clinical trial conducted in 2021 at the University of California, Davis, studied the use of ofatumumab and FFP in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). The researchers explained that many patients with CLL have low levels of complement and that, even though FDA has approved several drugs for use in this cancer, these drugs are often used as combination therapies, and many people, especially elderly patients, cannot tolerate the use of multiple drugs because of the side effects. Therefore, the researchers wanted to investigate a less toxic and more effective treatment option such as FFP therapy.

The main purpose of this study was to see if patients responded to FFP therapy and ofatumumab. Another purpose of the study was to learn if this therapy would increase the chances of curing patients of leukemia. The study also looked at the levels of complement in the participants’ blood, as the levels of complement might allow for a better understanding of whether increasing the levels of complement by giving FFP might help control leukemia.¹⁶

More Research Is Needed

While more research and clinical trials are needed before this up-and-coming therapy can be considered a routine cancer treatment, some plasma therapies are clearly already being used to treat many cancers with great success.